• The Korean Journal of Pain
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• v.33 no.1
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• pp.30-39
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• 2020

Background: This study examined the effects of gabexate mesilate on spinal nerve ligation (SNL)-induced neuropathic pain. To confirm the involvement of gabexate mesilate on neuroinflammation, we focused on the activation of nuclear factor-κB (NF-κB) and consequent the expression of proinflammatory cytokines and inducible nitric oxide synthase (iNOS). Methods: Male Sprague-Dawley rats were used for the study. After randomization into three groups: the sham-operation group, vehicle-treated group (administered normal saline as a control), and the gabexate group (administered gabexate mesilate 20 mg/kg), SNL was performed. At the 3rd day, mechanical allodynia was confirmed using von Frey filaments, and drugs were administered intraperitoneally daily according to the group. The paw withdrawal threshold (PWT) was examined on the 3rd, 7th, and 14th day. The expressions of p65 subunit of NF-κB, interleukin (IL)-1, IL-6, tumor necrosis factor-α, and iNOS were evaluated on the 7th and 14th day following SNL. Results: The PWT was significantly higher in the gabexate group compared with the vehicle-treated group (P < 0.05). The expressions of p65, proinflammatory cytokines, and iNOS significantly decreased in the gabexate group compared with the vehicle-treated group (P < 0.05) on the 7th day. On the 14th day, the expressions of p65 and iNOS showed lower levels, but those of the proinflammatory cytokines showed no significant differences. Conclusions: Gabexate mesilate increased PWT after SNL and attenuate the progress of mechanical allodynia. These results seem to be involved with the antiinflammatory effect of gabexate mesilate via inhibition of NF-κB, proinflammatory cytokines, and nitric oxide.

• Natural Product Sciences
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• v.21 no.3
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• pp.205-209
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• 2015

Fucoidan, a sulfated polysaccharide is found in several types of edible brown algae. It has shown numerous biological activities; however, the molecular mechanisms on the activity against atopic dermatitis have not been reported yet. We now examined the effects of fucoidan on chemokine production co-induced by TNF-α/IFN-γ, and the possible mechanisms underlying these biological effects. Our data showed that fucoidan inhibited the TNF-α/IFN-γ-induced production of thymus and activation-regulated chemokine (TARC) and macrophagederived chemokine (MDC) mRNA in human keratinocytes HaCaT cells. Also, fucoidan suppressed phosphorylation of nuclear factor kappa B (NF-κB) and activation of signal transducer and activator of transcription (STAT)1 in a dose-dependent manner. In addition, fucoidan significantly inhibited activation of extracellular-signal-regulated kinases (ERK) phosphorylation. These data indicate that fucoidan shows anti-inflammatory effects by suppressing the expression of TNF-α/IFN-γ-induced chemokines by blocking NF-κB, STAT1, and ERK1/2 activation, suggestive of as used as a therapeutic application in inflammatory skin diseases, such as atopic dermatitis.

• Biomolecules & Therapeutics
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• v.31 no.5
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• pp.544-549
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• 2023

In this study, artesunate, an antimalarial agent, was investigated for its potential effect on the gene expression of airway MUC5AC mucin. The human pulmonary epithelial NCI-H292 cells were pretreated with artesunate for 30 min and then stimulated with phorbol 12-myristate 13-acetate (PMA), for the following 24 h. The effect of artesunate on PMA-induced nuclear factor kappa B (NF-kB) signaling pathway was also examined. Artesunate inhibited the glycoprotein production and mRNA expression of MUC5AC mucins, induced by PMA through the inhibition of degradation of inhibitory kappa Bα (IkBα) and NF-kB p65 nuclear translocation. These results suggest artesunate suppresses the gene expression of mucin through regulation of NF-kB signaling pathway, in human pulmonary epithelial cells.

• Journal of Life Science
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• v.23 no.4
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• pp.471-478
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• 2013

Human adipose tissue-derived mesenchymal stem cells (hADSCs) have therapeutic potential, including the ability to self-renew and differentiate into multiple lineages. Understanding of molecular mechanisms of stem cell differentiation is important for improving the therapeutic efficacies of stem cell transplantation. In this study, we determined the role of nuclear factor of activated T cells (NFAT5) in the osteogenic differentiation of hADSCs. The down-regulation of NFAT5 expression by the transfection of a specific siRNA significantly inhibited osteogenic differentiation of hADSCs and decreased the activity of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-${\kappa}B$) promoter without affecting their proliferation and adipogenic differentiation. The inhibition of NFAT5 expression inhibited the basal and Tumor Necrosis Factor ${\alpha}$ (TNF-${\alpha}$) induced activation of NF-${\kappa}B$, but it did not affect TNF-${\alpha}$-induced degradation of the $I{\kappa}B$ protein. These findings indicate that NFAT5 plays an important role in the osteogenic differentiation of hADSCs through the modulation of the NF-${\kappa}B$ pathway.

• Archives of Pharmacal Research
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• v.29 no.7
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• pp.591-597
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• 2006

Aerial parts of Artemisia asiatica (Compositae) have been traditionally used as an oriental medicine for the treatment of inflammatory and ulcerogenic diseases. In the present study, artemisolide was isolated as a nuclear factor $(NF)-{\kappa}B$ inhibitor from A. asiatica by activity-guided fractionation. Artemisolide inhibited $NF-{\kappa}B$ transcriptional activity in lipopolysaccharide (LPS)-stimulated macrophages RAW 264.7 with an $IC_{50}$ value of $5.8\;{\mu}M$. The compound was also effective in blocking $NF-{\kappa}B$ transcriptional activities elicited by the expression vector encoding the $NF-{\kappa}B$ p65 or p50 subunits bypassing the inhibitory kB degradation signaling $NF-{\kappa}B$ activation. The macrophages markedly increased their $PGE_2$ and NO production upon exposure to LPS alone. Artemisolide inhibited LPS-induced $PGE_2$ and NO production with $IC_{50}$ values of $8.7\;{\mu}M$ and $6.4\;{\mu}M$, respectively, but also suppressed LPS-induced synthesis of cyclooxygenase (COX)-2 or inducible NO synthase (iNOS). Taken together, artemisolide is a $NF-{\kappa}B$ inhibitor that attenuates LPS-induced production of $PGE_2$ or NO via down-regulation of COX-2 or iNOS expression in macrophages RAW 264.7. Therefore, artemisolide could represent and provide the anti-inflammatory principle associated with the traditional medicine, A. asiatica.

• IMMUNE NETWORK
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• v.3 no.4
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• pp.310-319
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• 2003

Inflammatory mediators has been recognized as an important role in the pathogenesis of rheumatoid arthritis (RA). IL-17 is increasingly recognized as an important regulator of immune and inflammatory responses, including induction of proinflammatory cytokines and osteoclastic bone resorption. Evidence of the expression and proinflammatory activity of IL-17 has been demonstrated in RA synovium and in animal models of RA. However, the signaling pathways that regulate IL-17 production remain unknown. In the present study, we investigated the role of the phosphatidylinositol 3 kinase (PI3K)-Akt pathway in the regulation of IL-17 production in RA. PBMC were separated from RA (n=24) patients, and stimulated with various agents (anti CD3, anti CD28, PHA, ConA, IL-15). IL-17 levels were determined by sandwich ELISA and RT-PCR. The production of IL-17 was significantly increased in cells treated with anti-CD3 antibody, PHA, IL-15 or MCP-1 (P<0.05). ConA also strongly induced IL-17 production (P<0.001), whereas TNF-alpha, IL-1beta, IL-18 or TGF-beta did not. IL-17 was detected in the PBMC of patients with osteoarthritis (OA) but their expression levels were much lower than those of RA PBMC. Anti-CD3 antibody activated the PI3K-Akt pathway and activation of the PI3K-Akt pathway resulted in a pronounced augmentation of nuclear factor kappaB ($NF-{\kappa}B$). IL-17 production by activated PBMC in RA is completely or partially blocked in the presence of $NF-{\kappa}B$ inhibitor PDTC and PI3K-Akt inhibitor, wortmannin and LY294002, respectively. Whereas the inhibition of AP-1 and extracellular signal-regulated kinase (ERK)1/2 did not affect IL-17 production. These results provide new insight into that PI3K/Akt and $NF-{\kappa}B$ dependent signal transduction pathway could be involved in the overproduction of key inflammatory cytokine, IL-17 in rheumatoid arthritis.

• Food Science and Biotechnology
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• v.15 no.2
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• pp.303-307
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• 2006

Effect of Oenanthe javanica ethanol extract (OJE) on nuclear factor-${\kappa}B$ (NF-${\kappa}B$)-mediated inflammatory reaction in RAW 264.7 macrophage cells was investigated. The OJE dose-dependently inhibited secretions of tumor necrosis factor-${\alpha}$ (TNF-${\alpha}$) and prostaglandins $E_2\;(PGE_2)$ from lipopolysaccharide (LPS)-stimulated RAW 264.7 cells and blocked LPS-induced expression of cyclooxygenase-2. To clarify mechanistic basis for its inhibitions of NF-${\kappa}B$ and activator protein-1 (AP-1) activations, effects of OJE on activations of NF-${\kappa}B$ and AP-1 genes by luciferase reporter activity were examined. The LPS-stimulated activations of NF-${\kappa}B$ and AP-1 were significantly blocked by 400 and $600\;{\mu$}g/mL of OJE, implicating that OJE might regulate gene expression through more than one signaling pathway. Cytosolic degradation of I-${\kappa}B{\alpha}$ was inhibited by OJE dose-dependently, indicating that the nuclear translocation of p65 was inhibited by OJE. These findings suggest that the inhibition of LPS-stimulated COX-2 expression by OJE is due to its inhibition of NF-${\kappa}B$ activation by blocking I-${\kappa}B{\alpha}$ degradation, which may be mechanistic basis of anti-inflammatory effects of OJE.

• Natural Product Sciences
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• v.24 no.1
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• pp.28-35
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• 2018

Pulegone is a naturally occurring organic compound obtained from essential oils from a variety of plants. The aim of this study was to investigate the anti-inflammatory effects through the inhibitory mechanism of inducible nitric oxide synthase (iNOS), cyclooxygenase (COX-2), nuclear factor kappa B ($NF-{\kappa}B$), mitogen-activated protein kinases (MAPK) pathways and the activation of nuclear factor erythroid 2-related factor 2 (Nrf2)/ heme oxygenase (HO)-1 pathways in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. Results revealed that pulegone significantly inhibited NO production as well as iNOS and COX-2 expressions. Meanwhile, western blot analysis showed that pulegone down-regulated LPS-induced $NF-{\kappa}B$ and MAPKs activation in RAW 264.7 cells. Furthermore, the selected compound suppressed LPS-induced intracellular ROS production in RAW 264.7 cells, while the expression of stress response gene, HO-1, and its transcriptional activator, Nrf-2 was upregulated upon pulegone treatment. Taking together, these findings provided that pulegone inhibited the LPS-induced expression of inflammatory mediators via the down-regulation iNOS, COX-2, $NF-{\kappa}B$, and MAPKs signaling pathways as well as up-regulation of Nrf-2/HO-1 indicating that pulegone has a potential therapeutic and preventive application in various inflammatory diseases.

• The Korean Journal of Physiology and Pharmacology
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• v.7 no.2
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• pp.65-71
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• 2003

Increasing evidences suggest that ischemia-induced vascular damage is an integral step in the cascade of the cellular and molecular events initiated by cerebral ischemia. In the present study, employing a mouse brain endothelioma-derived cell line, bEnd.3, and oxygen-glucose deprivation (OGD) as an in vitro stroke model, the role of nuclear factor kappa B (NF-${\kappa}B$) activation during ischemic injury was investigated. OGD was found to activate NF-${\kappa}B$ and to induce bEnd.3 cell death in a time-dependent manner. OGD phosphorylated neither 32 Ser nor 42 Tyr of $I{\kappa}B{\alpha}$. OGD did not change the amount of $I{\kappa}B{\alpha}$. The extents of OGD-induced cell death after 8 h, 10 h, 12 h and 14 h of OGD were 10%, 35%, 60% and 85%, respectively. Reperfusion following OGD did not cause additional cell death, indicating no reperfusion injury after ischemic insult in cerebral endothelial cells. Three known as NF-${\kappa}B$ inhibitors, including pyrrolidine dithiocarbamate (PDTC) plus zinc, aspirin and caffeic acid phenethyl ester (CAPE), inhibited OGD-induced NF-${\kappa}B$ activation and increased OGD-induced bEnd.3 cell death in a dose dependent manner. There were no changes in the protein levels of bcl-2, bax and p53 which are modulated by NF-${\kappa}B$ activity. These results suggest that NF-${\kappa}B$ activation might be a protective mechanism for OGD-induced cell death in bEnd.3.

• Natural Product Sciences
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• v.23 no.1
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• pp.1-4
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• 2017

Sinensetin, a pentamethoxyflavone, is known to exert various pharmacological activities including anti-angiogenesis, anti-diabetic and anti-inflammatory activities. However, its effects on the human mast cell - 1 (HMC-1) mediated inflammatory mechanism remain unknown. To explore the mediator and cellular inflammatory response of sinensetin, we examined its influence on phorbol 12-myristate 13-acetate (PMA) plus A23187 induced inflammatory mediator production in a human mast cell line. In this study, interleukin (IL)-6 production was measured using the enzyme-linked immunosorbent assay and reverse transcription polymerase chain reaction. Sinensetin inhibited PMA plus A23187 induced IL-6 production in a dose-dependent manner as well as IL-4, IL-5 and IL-8 mRNA expression. Furthermore, sinensetin inhibited signal transducer and activator of transcription 3 (STAT3) phosphorylation, suggesting that sinensetin inhibits the production of inflammatory mediators by blocking STAT3 phosphorylation. Moreover, sinensetin was found to inhibit nuclear factor kappa B activation. These findings suggest that sinensetin may be involved in the regulation of mast cell-mediated inflammatory responses.